We are interested in the mechanism(s) of chromosomal rearrangements because they represent such profound examples of genomic instability. We also utilize the recognition of chromosomal rearrangements as useful tools in the diagnosis, staging, treatment planning, and risk assessment of individuals or populations predisposed to the development of cancer (see separate project). But the cloning and characterization of chromosomal abnormalities is also, for us, a starting point in the investigation of genes which play crucial roles in the growth and/or development of the cells in which the aberration occurs. That this be so is based on the concept that aberrations are more likely to occur in chromatin regions that are "open", active, and accessible. This premise has been the foundation of a successful program of gene identification and characterization within our laboratory. This strategy has led us to the discovery of six interesting and important human genes. Three of these genes, SCL, NHLH1, and NHLH2 are members of the basic domain-helix-loop- helix (bHLH) family of transcription factors, a family known to act in nodal points of tissue specific developmental processes. One of these genes, SCL, appears to play a role in early hematopoietic development, the other two are more likely to be active in early human nervous system development. We have also identified a gene, SIL, which forms a fusion message with SCL subsequent to an interstitial deletion of chromosome 1 in approximately 20% of children with T-cell acute lymphoblastic leukemia. We have shown that NHLH1 and NHLH2 are expressed in early neuronal development by tissue in situ hybridization of murine samples during fetal neural development, and in postnatal rat and mouse cerebellar tissue. We have cloned the homologous genes for SCL and NHLH1/2 from Drosophila melanogaster, mapped them to Drosophila chromosome X, and shown that they are both expressed during neural development in this more genetically defined organism. We have generated mice that are heterozygous +/- for the NHLH2 gene and are breeding them together to generate an "NHLH2 knockout" animal. We have generated mice that are chimeric for cells carrying a defective NHLH 1 gene and are looking to see if the defective allele can be passed in the germline. We have generated embryonic stem cell clones that have a defective SIL allele.